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2007 Grant - Georgakopoulos

Role of Presenilin-1/Gamma-Secretase in EphB-Induced Angiogenesis

Anastasios Georgakopoulos, Ph.D.
Mount Sinai School of Medicine
New York, New York

2007 Investigator-Initiated Research Grant

EphrinB is a protein found in the brain that is important for the growth and development of brain blood vessels. Under normal conditions, ephrinB is cleaved into fragments by another protein, gamma-secretase. One of the resulting fragments of ephrinB stimulates the growth of blood vessels. Interestingly, gamma-secretase is also strongly implicated in Alzheimer's disease, as this protein also produces beta-amyloid by cutting its parent protein. This latter action of gamma-secretase is regulated by another protein, presenilin-1.

Anastasios Georgakopolous, Ph.D., and colleagues have found that presenilin-1 also regulates the ability of gamma-secretase to cleave ephrinB. Indeed, if presenilin-1 is mutated, as occurs in some inherited forms of Alzheimer's disease, then gamma-secretase is unable to cleave ephrinB. Such a mutation might be expected to hinder the growth and development of blood vessels in the brain, possibly contributing to the development of Alzheimer's disease.

Dr. Georgakopolous has proposed to study how presenilin-1 regulates gamma-secretase, and how such regulation influences the production of ephrinB fragments. This work should improve our understanding of how presenilin-1, gamma-secretase and ephrinB control the growth and development of brain blood vessels. It should lead to a better understanding of the biochemical mechanisms that cause brain damage in persons with Alzheimer's disease.